tbuckley/cabot-search huggingface dataset:
Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials
Authors: Florence Delestre, Pierre Charles, Alexandre Karras, Christian Pagnoux, Antoine Néel, Pascal Cohen, Olivier Aumaître, Stanislas Faguer, Pierre Gobert, François Maurier, Maxime Samson, Pascal Godmer, Bernard Bonnotte, Vincent Cottin, Catherine Hanrotel-Saliou, Thomas Le Gallou, Pierre-Louis Carron, Hélène Desmurs-Clavel, Guillaume Direz, Noémie Jourde-Chiche, Francois Lifermann, Nicolas Martin-Silva, Grégory Pugnet, Thomas Quéméneur, Marie Matignon, Ygal Benhamou, Eric Daugas, Estibaliz Lazaro, Nicolas Limal, Maïzé Ducret, Antoine Huart, Jean-François Viallard, Eric Hachulla, Elodie Perrodeau, Xavier Puechal, Loïc Guillevin, Raphaël Porcher, Benjamin Terrier
Journal: Annals of the Rheumatic Diseases (2023)

Objective To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). Methods The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. Results 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). Conclusions According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.
<i>Helicobacter pylori</i>infection alters gut virome by expanding temperate phages linked to increased risk of colorectal cancer
Authors: Shiqi Luo, Jinlong Ru, Mohammadali Khan Mirzaei, Jinling Xue, Xue Peng, Anna Ralser, Joshua Lemuel Hadi, Raquel Mejías-Luque, Markus Gerhard, Li Deng
Journal: Gut (2023)
Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study
Authors: Yiming Luo, Marcela A Ferrada, Keith A Sikora, Cameron Rankin, Hugh D Alessi, Daniel L Kastner, Zuoming Deng, Mengqi Zhang, Peter A Merkel, Virginia B Kraus, Andrew S Allen, Peter C Grayson
Journal: Annals of the Rheumatic Diseases (2023)

Objective Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP. Methods We performed a case–control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth’s logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA. Results In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10 −7 ). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p&lt;0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB , RELA and REL using higher criticism test weighted by eigenvector centrality. Conclusions This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments.
Specific descriptions of axial involvement are associated with radiographic damage development after 2 years in psoriatic arthritis patients
Authors: Manouk de Hooge, Alla Ischenko, Serge Steinfeld, Adrien Nzeusseu, Dirk Elewaut, Rik Lories, Filip Van den Bosch, Kurt De Vlam
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Investigating the association between different definitions of axial involvement and syndesmophytes development over 2 years in patients with psoriatic arthritis (PsA). Methods Patients from a prospective multicentre cohort (Belgian Epidemiological Psoriatic Arthritis Study) involving 17 Belgian rheumatology practices were recruited between December 2012 and July 2014 and included when fulfilling the Classification Criteria for Psoriatic Arthritis. Axial involvement included six clinical and two radiographic oriented definitions. Two calibrated central readers evaluated radiographic damage by assessing the modified Stoke Ankylosing Spondylitis Spinal Score and modified New York criteria. New syndesmophytes after 2 years were described conditional on axial involvement at baseline. Logistic regression analyses were used to investigate the association between syndesmophyte development and axial involvement. All definitions of axial involvement were evaluated separately. Results From 150 patients, a 2-year follow-up of spinal radiographs was obtained. There are 11 patients with new syndesmophytes after 2 years. For the clinical definitions of axial involvement ‘global assessment’, ‘detailed assessment’, ‘back pain (BP)’ and ‘inflammatory BP (IBP)’ the probabilities of developing syndesmophytes ranged between 0.06 and 0.08 and were similar for the presence or absence of the definition. When including elevated C reactive protein (CRP) to the definitions the probability of developing syndesmophytes over 2 years increased two times for CBP and seven times for IBP. With radiographic axial involvement a similar trend was seen; radiographic sacroiliitis as definition showed a probability three times higher. When combined with elevated CRP there would be a 14 times higher chance to develop syndesmophytes in 2 years. The ORs varied from 0.83 to 13.80, though none of them were statistically significant. Conclusions The likelihood of syndesmophyte formation in PsA is low. The probability of developing syndesmophytes is much higher when axial involvement is determined radiographically rather than clinically, particularly in the context of high CRP.
Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade
Authors: Yan Luo, Barath Shreeder, James W Jenkins, Huashan Shi, Purushottam Lamichhane, Kexun Zhou, Deborah A Bahr, Sophia Kurian, Katherine A Jones, Joshua I Daum, Navnita Dutta, Brian M Necela, Martin J Cannon, Matthew S Block, Keith L Knutson
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. Methods ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. Results Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. Conclusions These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.
A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain
Authors: Christopher H. Chen, Leannah N. Newman, Amanda P. Stark, Katherine E. Bond, Dawei Zhang, Stefano Nardone, Charles R. Vanderburg, Naeem M. Nadaf, Zhiyi Yao, Kefiloe Mutume, Isabella Flaquer, Bradford B. Lowell, Evan Z. Macosko, Wade G. Regehr
Journal: Nature Neuroscience (2023)
Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis
Authors: Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, Jose Gonzalez-Gomariz, Celia Gomar, Joan Salvador Russo-Cabrera, Irene Olivera, Assunta Cirella, Myriam Fernandez-Sendin, Maite Alvarez, Alvaro Teijeira, Cigdem Atay, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses. Methods MVA encoding scIL-12 (MVA.scIL-12) was evaluated against peritoneal carcinomatosis models based on intraperitoneal engraftment of tumor cells. CD8-mediated immune responses, elucidated antitumor efficacy, and safety were evaluated following intravenous, intratumoral, or intraperitoneal administration of the viral vector. The immune response was measured by ELISpot (enzyme-linked immunosorbent spot), RNA sequencing, flow cytometry, intravital microscopy, and depletion of lymphocyte subsets with monoclonal antibodies. Safety was assessed by body-weight follow-up and blood testing. Tissue tropism on intravenous or intraperitoneal administration was assessed by bioluminescence analysis using a reporter MVA encoding luciferase. Results Intraperitoneal or locoregional administration, but not other routes of administration, resulted in a potent immune response characterized by increased levels of tumor-specific CD8 + T lymphocytes with the ability to produce both interferon-γ and tumor necrosis factor-α. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result of intraperitoneal treatment, a single administration of MVA.scIL-12 encoding scIL-12 completely eradicated MC38 tumors implanted in the peritoneal cavity and also protected cured mice from subsequent subcutaneous rechallenges. Bioluminescence imaging using an MVA encoding luciferase revealed that intraperitoneal administration targets transgene to the omentum. The omentum is considered a key tissue in immune protection of the peritoneal cavity. The safety profile of intraperitoneal administration was also better than that following intravenous administration since no weight loss or hematological toxicity was observed when the vector was locally delivered into the peritoneal cavity. Conclusion Intraperitoneal administration of MVA vectors encoding scIL-12 targets the omentum, which is the tissue where peritoneal carcinomatosis usually begins. MVA.scIL-12 induces a potent tumor-specific immune response that often leads to the eradication of experimental tumors disseminated to the peritoneal cavity.
Author Correction: Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease
Authors: Daniel K. Wilton, Kevin Mastro, Molly D. Heller, Frederick W. Gergits, Carly Rose Willing, Jaclyn B. Fahey, Arnaud Frouin, Anthony Daggett, Xiaofeng Gu, Yejin A. Kim, Richard L. M. Faull, Suman Jayadev, Ted Yednock, X. William Yang, Beth Stevens
Journal: Nature Medicine (2023)
Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial
Authors: Ken Mautner, Michael Gottschalk, Scott D. Boden, Alison Akard, Won C. Bae, Lora Black, Blake Boggess, Paramita Chatterjee, Christine B. Chung, Kirk A. Easley, Greg Gibson, Josh Hackel, Katie Jensen, Linda Kippner, Chad Kurtenbach, Joanne Kurtzberg, R. Amadeus Mason, Benjamin Noonan, Krishnendu Roy, Verle Valentine, Carolyn Yeago, Hicham Drissi
Journal: Nature Medicine (2023)

Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence II-IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737.
Age-related dysregulation of homeostatic control in neuronal microcircuits
Authors: Carola I. Radulescu, Nazanin Doostdar, Nawal Zabouri, Leire Melgosa-Ecenarro, Xingjian Wang, Sadra Sadeh, Pavlina Pavlidi, Joe Airey, Maksym Kopanitsa, Claudia Clopath, Samuel J. Barnes
Journal: Nature Neuroscience (2023)

Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.
Molecular blueprints for spinal circuit modules controlling locomotor speed in zebrafish
Authors: Irene Pallucchi, Maria Bertuzzi, David Madrid, Pierre Fontanel, Shin-ichi Higashijima, Abdeljabbar El Manira
Journal: Nature Neuroscience (2023)

Abstract The flexibility of motor actions is ingrained in the diversity of neurons and how they are organized into functional circuit modules, yet our knowledge of the molecular underpinning of motor circuit modularity remains limited. Here we use adult zebrafish to link the molecular diversity of motoneurons (MNs) and the rhythm-generating V2a interneurons (INs) with the modular circuit organization that is responsible for changes in locomotor speed. We show that the molecular diversity of MNs and V2a INs reflects their functional segregation into slow, intermediate or fast subtypes. Furthermore, we reveal shared molecular signatures between V2a INs and MNs of the three speed circuit modules. Overall, by characterizing how the molecular diversity of MNs and V2a INs relates to their function, connectivity and behavior, our study provides important insights not only into the molecular mechanisms for neuronal and circuit diversity for locomotor flexibility but also for charting circuits for motor actions in general.
SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
Authors: Nicolas Huot, Cyril Planchais, Pierre Rosenbaum, Vanessa Contreras, Beatrice Jacquelin, Caroline Petitdemange, Marie Lazzerini, Emma Beaumont, Aurelio Orta-Resendiz, Félix A. Rey, R. Keith Reeves, Roger Le Grand, Hugo Mouquet, Michaela Müller-Trutwin
Journal: Nature Immunology (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.
Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR–RUNX1
Authors: Li Zhou, Dongxiao Wu, Yabo Zhou, Dianheng Wang, Haixia Fu, Qiusha Huang, Guohui Qin, Jie Chen, Jiadi Lv, Shaoyang Lai, Huafeng Zhang, Ke Tang, Jingwei Ma, Roland Fiskesund, Yi Zhang, Xiaohui Zhang, Bo Huang
Journal: Nature Immunology (2023)

Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.
An atlas of genetic determinants of forearm fracture
Authors: Maria Nethander, Sofia Movérare-Skrtic, Anders Kämpe, Eivind Coward, Ene Reimann, Louise Grahnemo, Éva Borbély, Zsuzsanna Helyes, Thomas Funck-Brentano, Martine Cohen-Solal, Juha Tuukkanen, Antti Koskela, Jianyao Wu, Lei Li, Tianyuan Lu, Maiken E Gabrielsen, Reedik Mägi, Mari Hoff, Ulf H Lerner, Petra Henning, Henrik Ullum, Christian Erikstrup, Søren Brunak, Arnulf Langhammer, Tiinamaija Tuomi, Asmundur Oddsson, Kari Stefansson, Ulrika Pettersson-Kymmer, Sisse Rye Ostrowski, Ole Birger Vesterager Pedersen, Unnur Styrkarsdottir, Outi Mäkitie, Kristian Hveem, J Brent Richards, Claes Ohlsson
Journal: Nature Genetics (2023)

Abstract Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4 , revealed that Tac4 – / – mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16 , displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
Single-haplotype comparative genomics provides insights into lineage-specific structural variation during cat evolution
Authors: Kevin R. Bredemeyer, LaDeana Hillier, Andrew J. Harris, Graham M. Hughes, Nicole M. Foley, Colleen Lawless, Rachel A. Carroll, Jessica M. Storer, Mark A. Batzer, Edward S. Rice, Brian W. Davis, Terje Raudsepp, Stephen J. O’Brien, Leslie A. Lyons, Wesley C. Warren, William J. Murphy
Journal: Nature Genetics (2023)